Isoniazid Preventive Therapy in HIV-Infected Pregnant and Postpartum Women.

BACKGROUND: The safety, efficacy, and appropriate timing of isoniazid therapy to prevent tuberculosis in pregnant women with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy are unknown. METHODS: In this multicenter, double-blind, placebo-controlled, noninferiority trial, we randomly assigned pregnant women with HIV infection to receive isoniazid preventive therapy for 28 weeks, initiated either during pregnancy (immediate group) or at week 12 after delivery (deferred group). Mothers and infants were followed through week 48 after delivery. The primary outcome was a composite of treatment-related maternal adverse events of grade 3 or higher or permanent discontinuation of the trial regimen because of toxic effects. The noninferiority margin was an upper boundary of the 95% confidence interval for the between-group difference in the rate of the primary outcome of less than 5 events per 100 person-years. RESULTS: A total of 956 women were enrolled. A primary outcome event occurred in 72 of 477 women (15.1%) in the immediate group and in 73 of 479 (15.2%) in the deferred group (incidence rate, 15.03 and 14.93 events per 100 person-years, respectively; rate difference, 0.10; 95% confidence interval [CI], -4.77 to 4.98, which met the criterion for noninferiority). Two women in the immediate group and 4 women in the deferred group died (incidence rate, 0.40 and 0.78 per 100 person-years, respectively; rate difference, -0.39; 95% CI, -1.33 to 0.56); all deaths occurred during the postpartum period, and 4 were from liver failure (2 of the women who died from liver failure had received isoniazid [1 in each group]). Tuberculosis developed in 6 women (3 in each group); the incidence rate was 0.60 per 100 person-years in the immediate group and 0.59 per 100 person-years in the deferred group (rate difference, 0.01; 95% CI, -0.94 to 0.96). There was a higher incidence in the immediate group than in the deferred group of an event included in the composite adverse pregnancy outcome (stillbirth or spontaneous abortion, low birth weight in an infant, preterm delivery, or congenital anomalies in an infant) (23.6% vs. 17.0%; difference, 6.7 percentage points; 95% CI, 0.8 to 11.9). CONCLUSIONS: The risks associated with initiation of isoniazid preventive therapy during pregnancy appeared to be greater than those associated with initiation of therapy during the postpartum period. (Funded by the National Institutes of Health; IMPAACT P1078 TB APPRISE ClinicalTrials.gov number, NCT01494038.).

Individual and Composite Adverse Pregnancy Outcomes in a Randomized Trial on Isoniazid Preventative Therapy Among Women Living With Human Immunodeficiency Virus.

BACKGROUND: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1078, a randomized noninferiority study designed to compare the safety of starting isoniazid preventive therapy (IPT) in women living with human immunodeficiency virus (HIV) either during pregnancy or after delivery, showed that IPT during pregnancy increased the risk of composite adverse pregnancy outcomes, but not individual outcomes. Many known factors are associated with adverse pregnancy outcomes: these factors' associations and effect modifications with IPT and pregnancy outcomes were examined. METHODS: Pregnant women living with HIV from 8 countries with tuberculosis incidences >60/100 000 were randomly assigned to initiate 28 weeks of IPT either during pregnancy or at 12 weeks after delivery. Using univariable and multivariable logistic regression and adjusting for factors associated with pregnancy outcomes, composite and individual adverse pregnancy outcome measures were analyzed. RESULTS: This secondary analysis included 925 mother-infant pairs. All mothers were receiving antiretrovirals. The adjusted odds of fetal demise, preterm delivery (PTD), low birth weight (LBW), or a congenital anomaly (composite outcome 1) were 1.63 times higher among women on immediate compared to deferred IPT (95% confidence interval [CI], 1.15-2.31). The odds of fetal demise, PTD, LBW, or neonatal death within 28 days (composite outcome 2) were 1.62 times higher among women on immediate IPT (95% CI, 1.14-2.30). The odds of early neonatal death within 7 days, fetal demise, PTD, or LBW (composite outcome 3) were 1.74 times higher among women on immediate IPT (95% CI, 1.22-2.49). CONCLUSIONS: We confirmed higher risks of adverse pregnancy outcomes associated with the initiation of IPT during pregnancy, after adjusting for known risk factors for adverse pregnancy outcomes.

Effects of Pregnancy and Isoniazid Preventive Therapy on Mycobacterium tuberculosis Interferon Gamma Response Assays in Women With HIV.

BACKGROUND: Pregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity. METHODS: 944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations. RESULTS: From entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum. CONCLUSIONS: Decreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.

African Multi-Site 2-Year Neuropsychological Study of School-Age Children Perinatally Infected, Exposed, and Unexposed to Human Immunodeficiency Virus.

BACKGROUND: Children living with human immunodeficiency virus (HIV) are at neuropsychological risk for cognitive and motor dysfunction. However, few prospective, multi-site studies have evaluated neuropsychological outcomes longitudinally among perinatally infected African children who received early antiretroviral treatment (ART). METHODS: We enrolled 611 children aged 5 to 11 years at 6 sites (South Africa [3], Zimbabwe, Malawi, Uganda). Of these, there were 246 children living with HIV (HIV+) who were initiated on ART before 3 years of age in a prior clinical trial comparing nevirapine to lopinavir/ritonavir (International Maternal Pediatric Adolescent Acquired Immunodeficiency Syndrome Clinical Trials [IMPAACT] P1060); 183 age-matched, exposed but uninfected (HEU) children; and 182 unexposed and uninfected (HUU) children. They were compared across 3 assessment time points (Weeks 0, 48, and 96) on cognitive ability (Kaufman Assessment Battery for Children, second edition [KABC-II]), attention/impulsivity (Tests of Variables of Attention [TOVA]), motor proficiency (Bruininks-Oseretsky Test, second edition [BOT-2]), and on the Behavior Rating Inventory of Executive Function (BRIEF). The cohorts were compared using linear mixed models, adjusting for site, child's age and sex, and selected personal/family control variables. RESULTS: The HIV+ cohort performed significantly worse than the HEU and HUU cohorts for all KABC-II, TOVA, and BOT-2 performance outcomes across all 3 time points (P values < .001). The HUU and HEU cohorts were comparable. For the KABC-II planning/reasoning subtests, the HIV+ children showed less improvement over time than the HUU and HEU groups. The groups did not differ significantly on the BRIEF. CONCLUSIONS: Despite initiation of ART in early childhood and good viral suppression at the time of enrollment, the HIV+ group had poorer neuropsychological performance over time, with the gap progressively worsening in planning/reasoning. This can be debilitating for self-management in adolescence.

Association between caregiver depression symptoms and child executive functioning. Results from an observational study carried out in four sub-Saharan countries.

Depressive symptoms among HIV-positive (HIV+) women may negatively impact their health and possibly that of their young children through risk of compromised caregiving. We evaluated how depression symptoms in predominantly (97%) female caregivers relate to neurodevelopmental outcomes in their HIV affected children. Data come from the IMPAACT P1104s Study, an observational cohort across six sites in four countries: Zimbabwe, South Africa, Uganda and Malawi. Participants (n = 611) were 5-11-year-old children with HIV (HIV), HIV exposed uninfected (HEU), or HIV unexposed uninfected (HUU). Primary caregivers were assessed for depression with the Hopkins Symptom Checklist (HSCL) and children with Behavior Rating Inventory for Executive Function (BRIEF) parent-report, Kauffman Assessment Battery for Children II (KABC), Bruininks-Oseretsky Test of Motor Proficiency 2nd Ed. (BOT-2), Test of Variables of Attention (TOVA), Multiple Indicators Cluster Survey, Child Disability and Development scales (MICS-4). Caregivers with higher depression scores (>1.75 mean HSCL score) reported more executive function problems in their children, regardless of HIV status. All executive function scores were significantly (p < 0.001) associated with depressive symptomatology at baseline and across time. Caregiver depressive symptomatology was not associated with other assessed neurocognitive outcomes. These results highlight the potential impact of caregiver depression on child behavioral outcomes.

Changing Trends in Complications and Mortality Rates Among US Youth and Young Adults With HIV Infection in the Era of Combination Antiretroviral Therapy.

BACKGROUND: Combination antiretroviral therapy (cART) has resulted in a dramatic decrease in human immunodeficiency virus (HIV)-related opportunistic infections and deaths in US youth, but both continue to occur. METHODS: We estimated the incidence of complications and deaths in IMPAACT P1074, a long-term US-based prospective multicenter cohort study conducted from April 2008 to June 2014. Incidence rates of selected diagnoses and trends over time were compared with those from a previous observational cohort study, P219C (2004-2007). Causes of death and relevant demographic and clinical features were reviewed. RESULTS: Among 1201 HIV-infected youth in P1074 (87% perinatally infected; mean [standard deviation] age at last chart review, 20.9 [5.4] years), psychiatric and neurodevelopmental disorders, asthma, pneumonia, and genital tract infections were among the most common comorbid conditions. Compared with findings in P219C, conditions with significantly increased incidence included substance or alcohol abuse, latent tuberculosis, diabetes mellitus, atypical mycobacterial infections, vitamin D deficiency or metabolic bone disorders, anxiety disorders, and fractures; the incidence of pneumonia decreased significantly. Twenty-eight deaths occurred, yielding a standardized mortality rate 31.5 times that of the US population. Those who died were older, less likely to be receiving cART, and had lower CD4 cell counts and higher viral loads. Most deaths (86%) were due to HIV-related medical conditions. CONCLUSIONS: Opportunistic infections and deaths are less common among HIV-infected youth in the US in the cART era, but the mortality rate remains elevated. Deaths were associated with poor HIV control and older age. Emerging complications, such as psychiatric, inflammatory, metabolic, and genital tract diseases, need to be addressed.

Impact of CYP2B6 genotype, tuberculosis therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months of age.

OBJECTIVE: Dosing efavirenz (EFV) in children less than 3 years of age is challenging due to large variability in drug levels. This study evaluated differences in pharmacokinetics with tuberculosis (TB) therapy, formulation, age, and CYP2B6 genotype. DESIGN: Pharmacokinetic data from three IMPAACT/PACTG studies (P382, P1021, and P1070) for children initiating therapy less than 40 months of age were evaluated. METHODS: Pharmacokinetic data were combined in a population pharmacokinetic model. Exposure from the 2-week pharmacokinetic visit was compared with changes in viral RNA between the Week 0 and Week 4 visits. RESULTS: The model included 103 participants (19 on TB therapy). CYP2B6 516 genotype information was available for 82 participants (TT: 15, GT: 28, GG: 39). Median age at the first pharmacokinetic visit was 17.0 months (range: 2.0-39.0 months). Liquid formulation led to a 42% decrease in bioavailability compared with opened capsules. TB therapy (isoniazid and rifampin) led to a 29% decreased clearance, however Monte Carlo simulations demonstrated the majority of participants on TB therapy receiving standard EFV dosing to be in the target area under the curve range. Clearance was 5.3-fold higher for GG than TT genotype and 3.3-fold higher for GT than TT genotype. Age did not have a significant effect on clearance in the final model. Initial viral RNA decay was lower for patients in the lowest quartile of exposures (area under the curves) than for higher quartiles (P = 0.013). CONCLUSION: EFV dosing should account for CYP2B6 516 genotype and formulation, but does not require adjustment for concurrent TB therapy.

Pharmacokinetics and safety of early nevirapine-based antiretroviral therapy for neonates at high risk for perinatal HIV infection: a phase 1/2 proof of concept study.

BACKGROUND: With increasing intention to treat HIV as early as possible, evidence to confirm the safety and therapeutic drug concentrations of a nevirapine-based antiretroviral regimen in the early neonatal period is needed. This study aims to establish dosing of nevirapine for very early treatment of HIV-exposed neonates at high risk of HIV acquisition. METHODS: IMPAACT P1115 is a multinational phase 1/2 proof-of-concept study in which presumptive treatment for in-utero HIV infection is initiated within 48 h of birth in HIV-exposed neonates at high risk of HIV acquisition. Participants were neonates who were at least 34 weeks gestational age at birth and enrolled within 48 h of birth, born to women with presumed or confirmed HIV infection who had not received antiretrovirals during this pregnancy. The regimen consisted of two nucleoside reverse transcriptase inhibitors plus nevirapine dosed at 6 mg/kg twice daily for term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week and 6 mg/kg twice daily thereafter for preterm neonates (34 to <37 weeks gestational age). Here, we report the secondary outcomes of the study: nevirapine exposures in study weeks 1 and 2 and treatment-associated grade 3 or 4 adverse events at least possibly related to study treatment up to study week 4. A population pharmacokinetic model to assess nevirapine exposure was developed from dried blood spot and plasma nevirapine concentrations at study weeks 1 and 2. Nevirapine exposure was assessed in all patients with available blood samples and safety was assessed in all participants. This trial is registered at ClinicalTrials.gov (NCT02140255). FINDINGS: Between Jan 23, 2015, and Sept 4, 2017, 438 neonates were enrolled and included in analyses; 36 had in-utero HIV infection and 389 (89%) were born at term. Neonates without confirmed in-utero HIV infection received nevirapine for a median of 13 days (IQR 7-14). Measured dried blood spot nevirapine concentrations were higher than the minimum HIV treatment target (3 µg/mL) in 314 (90%, 95% CI 86-93) of 349 neonates at week 1 and 174 (87%, 81-91) of 201 at week 2. In Monte-Carlo simulations, week 1 nevirapine concentrations exceeded 3 µg/mL in 80% of term neonates and 82% of preterm neonates. DAIDS grade 3 or 4 adverse events at least possibly related to antiretrovirals occurred in 30 (7%, 95% CI 5-10) of 438 infants but did not lead to nevirapine cessation in any neonates; neutropenia (25 [6%] neonates) and anaemia (six [1%]) were most common. INTERPRETATION: Nevirapine at the dose studied was confirmed to be safe and provides therapeutic exposure concentrations. These data support nevirapine as a component of presumptive HIV treatment in high-risk neonates. FUNDING: National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Safety, immunogenicity, and transplacental antibody transport of conjugated and polysaccharide pneumococcal vaccines administered to pregnant women with HIV: a multicentre randomised controlled trial.

BACKGROUND: Pneumococcus remains an important cause of morbidity in pregnant women with HIV and their infants. We compared the safety and immunogenicity of PCV-10 and PPV-23 with placebo administered in pregnancy. METHODS: This double-blind, multicentre, randomised controlled trial was done at eight outpatient clinics in Brazil. Eligible participants were adult women with HIV who were pregnant at a gestational age between 14 weeks and less than 34 weeks and who were taking antiretroviral therapy at study entry. Participants were randomly assigned (1:1:1) to receive either PCV-10, PPV-23, or placebo. Participants and study teams were unaware of treatment allocation. Antibodies against seven vaccine serotypes in PCV-10 and PPV-23 were measured by ELISA. The primary outcomes were maternal and infant safety assessed by the frequency of adverse events of grade 3 or higher; maternal seroresponse (defined as ≥2-fold increase in antibodies from baseline to 28 days after immunisation) against five or more serotypes; and infant seroprotection (defined as anti-pneumococcus antibody concentration of ≥0·35 µg/mL) against five or more serotypes at 8 weeks of life. The study was powered to detect differences of 20% or higher in the primary immunological outcomes between treatment groups. This trial is registered with ClinicalTrials.gov, NCT02717494. FINDINGS: Between April 1, 2016, and Nov 30, 2017, we enrolled 347 pregnant women with HIV, of whom 116 were randomly assigned to the PCV-10 group, 115 to the PPV-23 group, and 116 to the placebo group. One participant in the PCV-10 group did not receive the vaccine and was excluded from subsequent analyses. The frequency of adverse events of grade 3 or higher during the first 4 weeks was similar in the vaccine and placebo groups (3% [90% CI 1-7] for the PCV-10 group, 2% [0-5] for the PPV-23 group, and 3% [1-8] for the placebo group). However, injection site and systemic grade 2 adverse reactions were reported more frequently during the first 4 weeks in the vaccine groups than in the placebo group (14% [9-20] for the PCV-10 group, 7% [4-12] for the PPV-23 group, and 3% [1-7] for the placebo group). The frequency of grade 3 or higher adverse effects was similar across maternal treatment groups (20% [14-27] for the PCV-10 group, 21% [14-28] for the PPV-23 group, and 20% [14-27] for the placebo group). Seroresponses against five or more serotypes were present in 74 (65%) of 114 women in the PCV-10 group, 72 (65%) of 110 women in the PPV-23 group, and none of the 113 women in the placebo group at 4 weeks post vaccination (p<0·0001 for PPV-23 group vs placebo and PCV-10 group vs placebo). Seroresponse differences of 20% or higher in vaccine compared with placebo recipients persisted up to 24 weeks post partum. At birth, 76 (67%) of 113 infants in the PCV-10 group, 62 (57%) of 109 infants in the PPV-23 group, and 19 (17%) of 115 infants in the placebo group had seroprotection against five or more serotypes (p<0·0001 for PPV-23 vs placebo and PCV-10 vs placebo). At 8 weeks, the outcome was met by 20 (19%) of 108 infants in the PCV-10 group, 24 (23%) of 104 infants in the PPV-23 group, and one (1%) of 109 infants in the placebo group (p<0·0001). Although a difference of 20% or higher compared with placebo was observed only in the infants who received PPV-23 at 8 weeks of life, the difference between the two vaccine groups was not appreciable. INTERPRETATION: PCV-10 and PPV-23 were equally safe and immunogenic in pregnant women with HIV and conferred similar levels of seroprotection to their infants. In areas in which childhood PCV administration decreased the circulation of PCV serotypes, PPV-23 administration to pregnant women with HIV might be more advantageous than PCV by virtue of including a broader range of serotypes. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development. TRANSLATION: For the Portuguese translation of the abstract see Supplementary Materials section.

Pharmacokinetics and Drug-Drug Interactions of Isoniazid and Efavirenz in Pregnant Women Living With HIV in High TB Incidence Settings: Importance of Genotyping.

The World Health Organization guidelines recommend that individuals living with HIV receive ≥ 6 months of isoniazid preventive therapy, including pregnant women. Yet, plasma isoniazid exposure during pregnancy, in the antiretroviral therapy era, has not been well-described. We investigated pregnancy-induced and pharmacogenetic-associated pharmacokinetic changes and drug-drug interactions between isoniazid and efavirenz in pregnant women. Eight hundred forty-seven women received isoniazid for 28 weeks, either during pregnancy or at 12 weeks postpartum, and 786 women received efavirenz. After adjusting for NAT2 and CYP2B6 genotype and weight, pregnancy increased isoniazid and efavirenz clearance by 26% and 15%, respectively. Isoniazid decreased efavirenz clearance by 7% in CYP2B6 normal metabolizers and 13% in slow and intermediate metabolizers. Overall, both isoniazid and efavirenz exposures were reduced during pregnancy, but the main determinants of drug concentration were NAT2 and CYP2B6 genotypes, which resulted in a five-fold difference for both drugs between rapid and slow metabolizers.

A prospective study of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected children from high prevalence countries.

BACKGROUND: The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected infants and young children is relatively understudied in regions endemic for HIV and TB. We aimed to describe incidence, clinical features and risk factors of pediatric IRIS in Sub-Saharan Africa and India. METHODS AND FINDINGS: We conducted an observational multi-centred prospective clinical study from December 2010 to September 2013 in children <72 months of age recruited from public antiretroviral programs. The main diagnostic criterion for IRIS was a new or worsening inflammatory event after initiating antiretroviral therapy (ART). Among 198 participants, median age 1.15 (0.48; 2.21) years, 38 children (18.8%) developed 45 episodes of IRIS. Five participants (13.2%) had two IRIS events and one (2.6%) had 3 events. Main causes of IRIS were BCG (n = 21; 46.7%), tuberculosis (n = 10; 22.2%) and dermatological, (n = 8, 17.8%). Four TB IRIS cases had severe morbidity including 1 fatality. Cytomegalovirus colitis and cryptococcal meningitis IRIS were also severe. BCG IRIS resolved without pharmacological intervention. On multivariate logistic regression, the most important baseline associations with IRIS were high HIV viral load (likelihood ratio [LR] 10.629; p = 0.0011), recruitment at 1 site (Stellenbosch University) (LR 4.01; p = 0.0452) and CD4 depletion (LR 3.4; p = 0.0654). Significantly more non-IRIS infectious and inflammatory events between days 4 and 17 of ART initiation were noted in cases versus controls (35% versus 15.2%: p = 0.0007). CONCLUSIONS: IRIS occurs commonly in HIV-infected children initiating ART and occasionally has severe morbidity. The incidence may be underestimated. Predictive, diagnostic and prognostic biomarkers are needed.

Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years.

BACKGROUND: CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection. METHODS: Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 µg × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks. RESULTS: Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) µg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) µg × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC. CONCLUSIONS: Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.

Validity of Neuropsychological Testing in Young African Children Affected by HIV.

INTRODUCTION: Western-constructed neuropsychological tests have been used in low and middle income countries to assess the impact of HIV/AIDS and other chronic illnesses. We explore using such instruments cross-culturally in a sub-Saharan Africa setting. METHODS: IMPAACT P1104S was a two-year observational study carried out at six clinical sites (South Africa- 3 sites, Malawi, Uganda and Zimbabwe) to assess and compare neuropsychological outcomes in three cohorts of children 5-11 years of age: HIV-infected (HIV), HIV-exposed but uninfected (HEU) and HIV unexposed and uninfected (HU). Descriptive statistics compared socio-demographic characteristics among children at sites. Instruments included the KABC-II cognitive ability, TOVA attention/impulsivity, BOT-2 motor proficiency tests, and BRIEF executive function problems. Test characteristics were assessed using intraclass and Spearman non-parametric correlations, linear regression and principal factor analyses. RESULTS: Of the 611 participants, 50% were male and mean age ranged from 6.6 to 8 years. In Malawi, Uganda and Zimbabwe, substantial proportions of families lived in rural settings in contrast to the South African sites. Intraclass correlation coefficients between weeks 0 and 48 were highest for the KABC scores, ranging between 0.42 to 0.71.Correlations among similar test domains were low to moderate but significant, with positive correlation between KABC Sequential and TOVA scores and negative correlation between BRIEF and KABC scores. TOVA response time scores correlated negatively with the BOT-2 Total points score. Strong and significant associations between individual measures of growth, disability and development with all test scores were observed. Performance-based measures were markedly lower for HIV compared to HEU and HU participants, even after controlling for age, sex and site. Factor analyses confirmed the underlying theoretical structure of the KABC scaled item scores. CONCLUSION: The KABC, TOVA, BRIEF and BOT-2 were valid and reliable tools for assessing the neuropsychological impact of HIV in four sub-Saharan African countries.

A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines.

BACKGROUND: The World Health Organization (WHO) recommends weight band dosing of antiretrovirals for children. Data are limited describing drug exposure/safety of lopinavir/ritonavir using WHO weight band dosing. METHODS: International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1083 was a phase II/III trial assessing the pharmacokinetics (PK) and short-term safety, tolerance and efficacy of lopinavir/ritonavir in human immunodeficiency virus-infected children 3-25 kg dosed according to WHO weight bands, with liquid solution or meltrex extrusion tablets. The main PK target was an area under the curve (AUC0-24) of 80-320 µg·h/mL. RESULTS: Of 97 enrolled participants, median age 2.5 years, 89 (91.8%) completed the protocol. Median LPV dose was 303 mg/m. The geometric mean (90% confidence limits) LPV PK AUC0-24 was 196 (177-217) µg·h/mL and Cmin was 2.47 (1.52-4.02) µg/mL. AUC0-24 was within the target range for 79% of participants. The median (Q1, Q3) difference between individual observed PK parameters and those expected if Food and Drug Administration dosing guidelines were followed was 30.7 (7.9, 54.3) for AUC0-24 and 0.56 (0, 1.27) for Cmin. Ten (10%) participants had grade 3 or 4 events deemed related to study treatment, mostly asymptomatic laboratory abnormalities. Three participants died of unrelated study treatment causes. At week 24, 57 of 79 (72%) participants reached viral suppression and the median increase in CD4% (n = 83) was 6.0 (P < 0.0001). CONCLUSIONS: WHO weight band dosing guidelines in children achieved adequate LPV plasma exposure but was higher than that expected with Food and Drug Administration dosing guidelines. Despite the higher LPV exposure, the treatment was well tolerated and the 24-week efficacy data were favorable.

Neuropsychological performance in African children with HIV enrolled in a multisite antiretroviral clinical trial.

OBJECTIVE AND DESIGN: Children with HIV infection (HIV+) are at neuropsychological risk, but few studies have evaluated this at multiple sites in low-income and middle-income countries. We compared neuropsychological outcomes at enrollment (>5 years age) among HIV+, HIV perinatally exposed uninfected (HEU), and HIV unexposed uninfected (HUU) children from four sub-Saharan countries. METHODS: IMPAACT P1060 compared nevirapine versus lopinavir/ritonavir-based antiretroviral treatment (ART) in HIV-infected children 6-35 months of age. The present study (P1104s) enrolled P1060 children at 5-11 years of age and evaluated their neuropsychological performance over 2 years using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II), Tests of Variables of Attention (TOVA), Bruininks-Oseretsky Test, 2nd edition (BOT-2), and parent-reported Behavior Rating Inventory of Executive Function (BRIEF). Cohorts were compared using generalized estimating equations least-squares means adjusted for site, child age and sex, and personal and social characteristics for child and caregiver. RESULTS: Six hundred and eleven (246 HIV+, 183 HEU, 182 HUU) of the 615 enrolled at six sites [South Africa (three), Zimbabwe, Malawi, Uganda] were available for analysis. Mean age was 7.2 years, 48% male, 69% in school. Unadjusted and adjusted comparisons were consistent. HIV+ children performed significantly worse than HEU and HUU cohorts on all KABC-II cognitive performance domains and on BOT-2 total motor proficiency (P < 0.001), but not on the BRIEF Global Executive Indices. HUU and HEU cohorts were comparable on cognitive outcomes. HIV+ children initiated on ART before 1 year of age had significantly better BRIEF evaluations (lower scores - fewer behavior problems), compared with those started after (P = 0.03). CONCLUSION: Significant cognitive deficits were documented among HIV+ children at school age, even when started on ART at an early age. Earlier HIV treatment, neuropsychological monitoring, and rehabilitative interventions are all needed. Subsequent testing for 2 more years will help further evaluate how HIV infection and exposure affect the developmental trajectory.

Impact of partner abuse on women's reproductive lives.

OBJECTIVE: To increase our understanding of how intimate partner abuse may limit women's reproductive choices. METHODS: Findings were obtained from a larger study involving interviews with 38 women participating in a hospital-based domestic violence program. We asked participants whether and in what ways their abusive partners had limited their ability to choose whether or not to have children. Content analysis was used to identify main themes. RESULTS: Thirteen (34%) participants reported that partners had limited their ability to choose whether or not to have children. Seven of these women described tactics to try to get them to have children, and 7 reported being pressured or forced to have abortions (1 woman reported both). Two women underwent sterilization in response to the abuse. Four of the 13 women reported contradictory behaviors by their partners around family planning, such as not allowing birth control, then demanding that the participant terminate the pregnancy. CONCLUSION: Women described several ways in which their abusive partners controlled or attempted to control their reproductive lives that have received little or no prior attention. Further studies are needed to determine the prevalence and consequences of these behaviors, particularly the extent to which women in abusive relationships feel coerced into sterilization or abortion.

Antimicrobial-specific cell-mediated immune reconstitution in children with advanced human immunodeficiency virus infection receiving highly active antiretroviral therapy.

To identify virological and immunological correlates of microbial-specific immune reconstitution in children with advanced human immunodeficiency virus (HIV) infection, Candida- and tetanus-specific lymphocyte proliferation was measured in 165 children initiating a new highly active antiretroviral therapy (HAART) regimen. During the study, the proportions of children with immunity to Candida and tetanus increased from 53% to 66% and 19% to 22%, respectively. Tetanus immunity was associated with an HIV load < or =400 RNA copies/mL and with Candida immunity. At the end of the study, 23% of the patients with baseline negative lymphocyte proliferation had tetanus immunity, and 65% had Candida immunity. Reconstitution of tetanus immunity correlated with lower end-of-study HIV loads and activated CD8+ cell percentages and higher baseline and in-study CD4+ cell percentages, but not with a gain of CD4+ cells. Reconstitution of Candida immunity showed similar trends. In conclusion, children with advanced HIV infection receiving HAART reconstituted Candida immunity more readily than they did tetanus immunity, suggesting a role for antigen reexposure. Additional factors for immune reconstitution were low HIV load, high CD4+ cell percentages, and low levels of activated CD8+ cells.

Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with and without prior nevirapine exposure for the prevention of mother-to-child HIV transmission.

BACKGROUND: In a randomized trial comparing nevirapine (NVP)-based versus lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) in HIV-infected children [primary endpoint discontinuation of study treatment for any reason or virologic failure by week 24] aged 2 months to 3 years, we assessed whether clinical, virologic, immunologic and safety outcomes varied by prior single-dose NVP exposure (PrNVP) for prevention of mother-to-child HIV transmission and other covariates. METHODS: Efficacy was assessed by time to ART discontinuation or virologic failure, virologic failure/death and death; safety by time to ART discontinuation because of a protocol-defined toxicity and first ≥ grade 3 adverse event; immunology and growth by changes in CD4%, weight/height World Health Organization z-scores from entry to week 48. Cox proportional hazards and linear regression models were used to test whether treatment differences depended on PrNVP exposure and other covariates. RESULTS: Over a median follow up of 48 (PrNVP) and 72 (no PrNVP) weeks, there was no evidence of differential treatment effects by PrNVP exposure or any other covariates. LPV/r-based ART was superior to NVP-based ART for efficacy and safety outcomes; however, those on NVP had larger improvements in CD4%, weight and height z-scores. Lower pretreatment CD4% and higher HIV-1 RNA levels were associated with reduced efficacy, lower pretreatment CD4% with shorter time to ART discontinuation because of a protocol-defined toxicity, and no PrNVP with shorter time to first grade ≥ 3 adverse event. CONCLUSIONS: Differences between LPV/r and NVP ART in efficacy, safety, immunologic and growth outcomes did not depend on PrNVP exposure, prior breast-feeding, sex, HIV-1 subtype, age, pretreatment CD4%, HIV-1 RNA or World Health Organization disease stage. This finding should be considered when selecting an ART regimen for young children.

Perceived changes in health and safety following participation in a health care-based domestic violence program.

This descriptive study explores perceived changes in health and safety and the potential process by which these changes occur. Forty-nine women experiencing intimate partner abuse participated in a health care-based domestic violence (DV) advocacy program for 6 months or more. An analysis of structured interviews in English and Spanish found that the majority of participants perceived positive changes in their personal safety and emotional health because of their involvement in the program. Some participants also perceived improvements in their physical health, unhealthy coping behaviors (e.g., overeating and smoking), and health care following program involvement. Participants' responses suggest a process of change whereby DV advocacy services first contribute to improved safety and emotional health, which then facilitates behavioral changes. Behavioral changes may subsequently contribute to improvements in physical health, which may also benefit emotional health. Longitudinal evaluations are needed to evaluate the impact of DV advocacy and other interventions for partner abuse on women's health and safety over time.

Impaired immunity to recall antigens and neoantigens in severely immunocompromised children and adolescents during the first year of effective highly active antiretroviral therapy.

BACKGROUND: We studied whether severely immunocompromised, human immunodeficiency virus (HIV)-infected children who were beginning highly active antiretroviral therapy (HAART) or changing HAART regimens could spontaneously respond to a recall antigen (tetanus toxoid [TT] vaccine) or respond to a recall antigen and neoantigen (hepatitis A virus [HAV] vaccine) after 3 vaccinations. METHODS: A total of 46 children who had CD4 cell percentages <15% and who demonstrated a >0.75-log reduction in plasma HIV RNA levels within 4 weeks of starting HAART were randomized to receive vaccinations with either TT or HAV vaccines during the first 6 months of HAART. Study subjects then received the alternate vaccine during the next 6 months of HAART. RESULTS: Despite the early decline in viremia and the later increase in the percentage of CD4 T cells, spontaneous recovery of cell-mediated immunity (CMI) was not seen for TT. Serologic responses to TT required 3 vaccinations and were comparable in both groups. Serologic responses to HAV were infrequent and of low titer, although the group that received HAV vaccine after receiving TT vaccine performed somewhat better. CMI to HAV was virtually absent. CONCLUSIONS: Severely immunocompromised children who are receiving HAART develop CMI and antibody to a recall antigen independent of the timing of vaccination, but they require a primary series of vaccinations. Antibodies to a neoantigen, HAV, developed when vaccination was delayed after initiation of HAART. CMI to a neoantigen was difficult to establish. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00004735/PACTG P1006 .